Ruolo di Souvenaid

Souvenaid contiene una combinazione di nutrienti unica e brevettata, denominata Fortasyn Connect™, sviluppata per favorire la formazione delle sinapsi.

LEGENDA

La combinazione di nutrienti attivi in Souvenaid si chiama Fortasyn Connect™

Questa combinazione unica di nutrienti ha dimostrato in studi clinici randomizzati, in doppio cieco vs. placebo di favorire la formazione delle sinapsi.

I nutrienti agiscono sinergicamente per promuovere la sintesi dei fosfolipidi [9]. La fosfatidilcolina, il fosfolipide più abbondante nel cervello, si forma principalmente attraverso una via metabolica ben conosciuta, nota come ciclo di Kennedy [10].

LEGENDA

La via metabolica di Kennedy [10]: la formazione di fosfatidilcolina prevede tre reazioni enzimatiche sequenziali. Nella prima, un monofosfato viene trasferito alla colina, portando alla formazione della fosfocolina. Nella seconda, la citidina-5-monofosfato viene trasferita dalla citidina trifosfato alla fosfocolina, portando a citidina difosfato-colina (CDP-colina). In ultimo, la citidina difosfato-colina e il diacilglicerolo (DAG) si legano a formare la fosfatidicolina, il fosfolipide più abbondante nelle membrane neuronali.

PUFA = acidi grassi polinsaturi omega-3; UMP = uridina monofosfato

I livelli dei nutrienti necessari per sostenere questa via metabolica appaiono ridotti nella malattia di Alzheimer [11-13].

La produzione di nuove membrane neuronali attraverso questa via metabolica è positivamente influenzata dall'aumento della disponibilità dei prcursori nutrizionali uridina, colina e omega 3. [9]. Inoltre, negli studi pre-clinici, si è osservato che arricchendo la dieta di alcuni nutrienti si ha un aumento delle spine dendritiche, delle proteine sinaptiche e della crescita del neurite, tutti prerequisiti per la formazione delle sinapsi [14-17]. Gli effetti maggiori sono stati osservati quando sono state usate combinazioni di nutrienti [9, 17-19]. In modelli pre-clinici, si è visto che la somministrazione di questi nutrienti migliora anche la comprensione e la memoria [19-24]. Questi risultati hanno fornito il razionale scientifico per la formulazione di Souvenaid.

Souvenaid è caratterizzato da precursori nutrizionali e cofattori che agiscono sinergicamente per favorire la formazione delle sinapsi:

acido docosaesanoico (DHA), acido eicosapentaenoico (EPA), uridina monofosfato (UMP) e colina sono precursori richiesti per promuovere la formazione della membrana neuronale [25];vitamine B e fosfolipidi agiscono come cofattori, aumentando la biodisponibilità dei precursori.

La specifica combinazione di questi nutrienti può sostenere la formazione delle membrane neuronali, aumentando la sintesi di fosfatidilcolina [9, 14-18].

Studi clinici hanno dimostrato che i singoli nutrienti non sono in grado di creare lo stesso beneficio:

 

• N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13.

Vitamin E and donepezil for the treatment of mild cognitive impairment. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ; Alzheimer's Disease Cooperative Study Group.

Source

Mayo Clinic College of Medicine, Rochester, Minn, USA.

Conclusion: Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.
www.ncbi.nlm.nih.gov/pubmed

• Arch Intern Med. 2006 Dec 11-25;166(22):2462-8.

A randomized trial of vitamin E supplementation and cognitive function in women. Kang JH, Cook N, Manson J, Buring JE, Grodstein F.

Source

Channing Laboratory, Boston, MA 02115, USA. nhjhk@channing.harvard.edu

Conclusion: Long-term use of vitamin E supplements did not provide cognitive benefits among generally healthy older women.

www.ncbi.nlm.nih.gov/pubmed

• JAMA. 2008 Oct 15;300(15):1774-83. doi: 10.1001/jama.300.15.1774.

High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease Cooperative Study.

Source

Department of Neurosciences, University of California, San Diego, 9500 Gilman Dr, M/C 0949, La Jolla, CA 92093, USA. paisen@ucsd.edu

Conclusion: This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.

www.ncbi.nlm.nih.gov/pubmed

• A Controlled Trial of Homocysteine Lowering and Cognitive Performance

Jennifer A. McMahon, Ph.D., Timothy J. Green, Ph.D., C. Murray Skeaff, Ph.D., Robert G. Knight, Ph.D., Jim I. Mann, Ph.D., and Sheila M. Williams, D.Sc.

N Engl J Med 2006; 354:2764-2772June 29, 2006DOI: 10.1056/NEJMoa054025

CONCLUSIONS: The results of this trial do not support the hypothesis that homocysteine lowering with B vitamins improves cognitive performance. (Australian Clinical Trials registry number, ACTR NO 12605000030673.)

www.nejm.org

• Clinical Trials | July 2012

Antioxidants for Alzheimer Disease A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures Douglas R. Galasko, MD; Elaine Peskind, MD; Christopher M. Clark, MD; Joseph F. Quinn, MD; John M. Ringman, MD; Gregory A. Jicha, MD, PhD; Carl Cotman, PhD; Barbara Cottrell, BS; Thomas J. Montine, MD, PhD; Ronald G. Thomas, PhD; Paul Aisen, MD; for the Alzheimer's Disease Cooperative StudyArch Neurol. 2012;69(7):836-841. doi:10.1001/archneurol.2012.85.

Conclusions: Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted.

Trial Registration clinicaltrials.gov Identifier: NCT00117403

archneur.jamanetwork.com

• J Alzheimers Dis. 2010;22(1):205-24. doi: 10.3233/JAD-2010-090940.

B-vitamins and fatty acids in the prevention and treatment of Alzheimer's disease and dementia: a systematic review. Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith L, Hawkesworth S, Vellas B.

Source

Nutrition and Public Health Intervention Research Unit, Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK. alan.dangour@lshtm.ac.uk

The results of intervention studies examining the effects of folic acid or fatty acid supplementation on cognitive function are inconsistent. In summary, the available evidence is insufficient to draw definitive conclusions on the association of B vitamins and fatty acids with cognitive decline or dementia, and further long-term trials are required.

www.ncbi.nlm.nih.gov/pubmed

• JAMA. 2010 Nov 3;304(17):1903-11. doi: 10.1001/jama.2010.1510.

Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J, Jack CR Jr, Weiner M, Shinto L, Aisen PS.

Source

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA. quinnj@ohsu.edu

Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT00440050.

www.ncbi.nlm.nih.gov/pubmed

• Arch Neurol. 2006 Oct;63(10):1402-8.

Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J.

Source

Department of Neurobiology, Caring Sciences and Society, Section of Clinical Geriatrics, Karolinska University Hospital Huddinge, Stockholm.

Conclusion: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE >27 points).

www.ncbi.nlm.nih.gov/pubmed

Bibliografia

1. Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298:789-91.
2. Scheff SW, Price DA, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging. 2006;27:1372-84.
3. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-80.
4. Terry RD. Alzheimer's disease and the aging brain. J Geriatr Psychiatry Neurol 2006;19:125-8.
5. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:280–92.
6. Yi JJ, Ehlers MD. Ubiquitin and protein turnover in synapse function. Neuron. 2005;47:629-32.
7. Lardi-Studler B, Fritschy JM. Matching of pre- and postsynaptic specializations during synaptogenesis. Neuroscientist. 2007;13:115-26.
8. Sastry PS. Lipids of nervous tissue: composition and metabolism. Prog Lipid Res 1985;24:69-176.
9. Wurtman RJ, Ulus IH, Cansev M, Watkins CJ, Wang L, Marzloff G. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006;1088:83-92.
10. Kennedy EP, Weiss SB. The function of cytidine coenzymes in the biosynthesis of phospholipides. J Biol Chem 1956;222:193-214.
11. Igarashi M, Ma K, Gao F, Kim HW, Rapoport SI, Rao JS. Disturbed Choline Plasmalogen and Phospholipid Fatty Acid Concentrations in Alzheimer's Disease Prefrontal Cortex. JAD 2011; 24, 507-517.
12. Pettegrew JW, Panchalingam K, Hamilton RL, McClure RJ. Brain membrane phospholipid alterations in Alzheimer's disease. Neurochem Res 2001 26, 771-782.
13. Mulder C, Wahlund LO, Teerlink T, Blomberg M, Veerhuis R, van Kamp GJ, Scheltens P, Scheffer PG. Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer's disease. J Neural Transm 2003; 110, 949-955.
14. Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007;1182:50-9.
15. Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27:137-45.
16. Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 [corrected]. Neuroscience. 2005;134(1):207-14.
17. Cansev M, Marzloff G, Sakamoto T, Ulus IH, Wurtman RJ. Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci. 2009;31:181-92.
18. Savelkoul PJ, Janickova H, Kuipers AA, Hageman RJ, Kamphuis PJ, Dolezal V, Broersen LM. A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro. J Neurochem. 2012;120:631-40.
19. Holguin S, Martinez J, Chow C, Wurtman R. Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. FASEB J. 2008;22:3938-46.
20. Teather LA, Wurtman RJ. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J Nutr. 2006;136:2834-7.
21. de Wilde MC, Hogyes E, Kiliaan AJ, Farkas T, Luiten PG, Farkas E. Dietary fatty acids alter blood pressure, behavior and brain membrane composition of hypertensive rats. Brain Res. 2003;988:9-19.
22. de Wilde MC, Farkas E, Gerrits M, Kiliaan AJ, Luiten PG. The effect of n-3 polyunsaturated fatty acid-rich diets on cognitive and cerebrovascular parameters in chronic cerebral hypoperfusion. Brain Res. 2002;94:166-73.
23. De Bruin NM, Kiliaan AJ, De Wilde MC, Broersen LM. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiol Learn Mem. 2003;80:63-79.
24. de Wilde MC, Penke B, van der Beek EM, Kuipers AA, Kamphuis PJ, Broersen LM. Neuroprotective effects of a specific multi-nutrient intervention against Aβ42-induced toxicity in rats. J Alzheimers Dis. 2011;27:327-39.
25. Scheltens P, Twisk JWR, Blesa R, Scarpini E, von Arnim CAF, Bongers A, Harrison J, Swinkels SHN, Stam CJ, de Waal H, Wurtman RJ, Wieggers RL, Vellas B, Kamphuis PJGH. Efficacy of Souvenaid in mild Alzheimer's disease – results from a randomised, controlled trial. J Alzheimers Dis (in press)
26. Scarmeas N, Stern Y, Mayeux R, Luchsinger JA. Mediterranean diet, Alzheimer disease, and vascular mediation. Arch Neurol 2006;63:1709-1717.
27. Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N. Food Combination and Alzheimer Disease Risk: A Protective Diet. Arch Neurol, 2010.2084.
28. Glasø M, Nordbø G, Diep L, Bøhmer T. Reduced concentrations of several vitamins in normal weight patients with late-onset dementia of the Alzheimer type without vascular disease. J Nutr Health Aging. 2004;8:407-13.
29. Köseoglu E, Karaman Y. Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. Clin Biochem. 2007;40:859-63.
30. Polidori MC, Mattioli P, Aldred S, Cecchetti R, Stahl W, Griffiths H, Senin U, Sies H, Mecocci P. Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia. Dement Geriatr Cogn Disord. 2004;18:265-70.
31. Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH. Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment. Lipids. 2000;35:1305-12.
32. Ravaglia G, Forti P, Maioli F, Bianchi G, Martelli M, Talerico T, Servadei L, Zoli M, Mariani E. Plasma amino acid concentrations in patients with amnestic mild cognitive impairment or Alzheimer disease. Am J Clin Nutr. 2004;80:483-8.
33. Corrigan FM, Van Rhijn AG, Ijomah G, McIntyre F, Skinner ER, Horrobin DF, Ward NI. Tin and fatty acids in dementia. Prostaglandins Leukot Essent Fatty Acids. 1991;43:229-38.
34. Corrigan FM, Horrobin DF, Skinner ER, Besson JA, Cooper MB. Abnormal content of n-6 and n-3 long-chain unsaturated fatty acids in the phosphoglycerides and cholesterol esters of parahippocampal cortex from Alzheimer's disease patients and its relationship to acetyl CoA content. Int J Biochem Cell Biol 1998; 30, 197-207